14-3-3 proteins are phosphoserine/threonine-binding molecules that interact with many regulatory proteins critical for cell death and survival. Recent research has established 14-3-3 proteins as critical regulators of survival signaling network in many cell types. Clinical evaluations have revealed 14-3-3 expression as an important prognostic parameter for poor survival in colorectal and pancreatic cancer patients. However, whether 14-3-3-mediated signaling pathway is essential for lung cancer survival, whether inhibition of the 14-3-3 prosurvival function can alter lung cancer cell sensitivity to chemotherapeutic agents, and whether 14-3-3 isoforms have any prognostic value for lung cancer patients remain unknown. Our proposal aims to translate the basic understanding into clinical gains for enhancing the therapeutic efficacy in lung cancer, as a component of an integrated P01 program project. We will test the hypothesis that 14-3-3 supports survival of lung cancer cells by suppressing the proapoptotic activity of its associated proteins. We will specifically test whether disruption of 14-3-3/ligand interactions predisposes lung cancer cells to apoptosis and whether 14-3-3 inhibitors sensitize lung cancer cells to chemotherapeutic agents such as mTOR and microtubule inhibitors. Further, we will examine whether expression of 14-3-3 isoforms has any prognostic value for lung cancer patient survival and whether 14-3-3 isoform expression in lung cancer patients is a predictive marker for therapeutic response. Disruption of 14-3-3/ligand interactions may provide a novel strategy to block upregulated survival signaling in lung cancer cells, thus limiting clonal expansion and reversing resistance to cancer therapies. Isolation of small molecule inhibitors of 14-3-3 together with our mechanistic investigations may lead to development of an entirely new class of potential anticancer agents which will impact multiple signaling pathways in a fashion similar to HSP90 inhibitors. In addition, the frequency of 14-3-3 abnormalities will be prospectively established for the field of cancer drug development